Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

Abstract

Background: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.

Methods: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.

Results: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.

Conclusions: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Figure 1. Response to 19–28z T Cells.

Panel A shows the rate of minimal residual disease (MRD)–positive or MRD-negative complete remission and no response. Patients for whom MRD status was unknown were included with those who had MRD-positive complete remission. Panel B shows the correlation between chimeric antigen receptor (CAR) T-cell expansion after infusion and the occurrence of complete remission (P<0.00l). The red line indicates the median. Solid circles indicate patients with CAR T-cell proliferation, and open circles patients with no CAR T-cell proliferation. VCN denotes vector copy number. Panel C shows the rate of complete remission according to demographic and clinical characteristics of the patients and characteristics of the disease at baseline. Squares represent the observed proportions, and the lines extending from the squares are the 95% confidence intervals for these proportions. The confidence intervals that are reported as numbers to the right of the plot are 95% confidence intervals for the difference of proportions from the reference category. Reference categories are identified by the absence of 95% confidence intervals. HSCT denotes hematopoietic stem-cell transplantation, and Ph Philadelphia chromosome.

Figure 2 (facing page).. Cytokine Release Syndrome and Neurotoxic Effects after Infusion of 19–28z T Cells.

Panels A and B show the rate of severe cytokine release syndrome and neurotoxic effects according to demographic and clinical characteristics of the patients and characteristics of the disease at baseline. A high disease burden was defined as 5% or more bone marrow blasts or extramedullary disease, and a low disease burden as less than 5% bone marrow blasts. P values were not adjusted for multiple comparisons. Squares represent the observed proportions and the lines extending from the squares are the 95% confidence intervals for these proportions. The confidence intervals reported as numbers to the right of the plot are 95% confidence intervals for the difference of proportions from the reference category. Reference categories are identified by the absence of the 95% confidence intervals. The peak CAR T-cell expansion after infusion significantly correlated with the incidence of neurotoxic effects (P<0.001) (Panel D) but not with severe cytokine release syndrome (P = 0.06) (Panel C). The red line indicates the median. CNS denotes central nervous system.

Figure 3 (facing page).. Event-free Survival and Overall Survival.

Panels A and B show event-free survival and overall survival, respectively, among all the patients. The median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Tick marks indicate censored data, and dashed lines 95% confidence intervals. Panels C and D show event-free survival and overall survival, respectively, according to status with regard to minimal residual disease (MRD) and response. Among patients who had an MRD-negative complete remission after the infusion of 19–28z T cells, the median event-free survival was 12.5 months (95% CI, 6.3 to 20.1) and the median overall survival was 20.7 months (95% CI, 15.3 to not reached). Among patients who had an MRD-positive complete remission or no response, the median event-free survival was 3.1 months (95% CI, 2.5 to 6.7) and the median overall survival was 6.6 months (95% CI, 3.0 to not reached). Panels E and F show event-free survival and overall survival, respectively, among patients who had an MRD-negative complete remission after the infusion of 19–28z CAR T cells according to whether the patient subsequently underwent allogeneic HSCT or did not.

Figure 4.. Event-free Survival and Overall Survival, According to Pretreatment Disease Burden.

Patients with a low disease burden (<5% bone marrow blasts) at the time of T-cell infusion had significantly longer event-free survival (Panel A) and overall survival (Panel B) than did those with a high disease burden (≥5% bone marrow blasts or extramedullary disease). The median event-free survival among patients with a low disease burden was 10.6 months (95% CI, 5.9 to not reached), as compared with 5.3 months (95% CI, 3.0 to 9.0) among patients with a high disease burden (P = 0.01). The median overall survival among patients with a low disease burden was 20.1 months (95% CI, 8.7 to not reached), as compared with 12.4 months (95% CI, 5.9 to 20.7) among those with a high disease burden (P = 0.02).